1. Field of Invention
This invention relates to N-oxide prodrug derivatives of 3-hydroxy morphinan and partial morphinan analgesics, agonist-antagonists, and narcotic antagonists having improved oral bioavailability, as well as pharmaceutical compositions comprising these compounds and suitable pharmaceutical carriers, methods of treating pain or reversing the effects of narcotic drugs such as morphine in a mammal using the prodrugs, and methods for preparing the prodrugs.
2. Background Art
The psychological and other medicinal properties of opium have been known since ancient times. It was not until the beginning of the nineteenth century, however, that morphine was isolated from opium. Codeine and papaverine were isolated not long thereafter, and by the middle of the nineteenth century, use of the pure alkaloids rather than crude opium preparations was becoming established medical practice.
Morphine and codeine are by far the most important naturally occurring opium alkaloids. They share the phenanthrene or morphinan ring structure. Since the morphine structure was elucidated in the early part of this century, a host of semisynthetic and synthetic derivatives have been prepared. A major focus of this research has been to find strong analgesic compounds without the abuse potential, physical-dependence and tolerance-producing characteristics that limit the usefulness of the opium alkaloids.
Another important goal in preparing derivatives of morphine has been to find potent analgesic compounds with improved oral efficacy. Due to significant first-pass metabolism in the liver and intestinal wall, many 3-hydroxy morphinans are significantly less effective orally than parenterally. For this reason, many 3-hydroxy morphinans, including morphine and buprenorphine, are administered mainly by injection. Codeine, on the other hand, has a much higher oral: parenteral potency ratio than morphine. Structurally, codeine is simply 3-methyl-morphine. The action of morphine is terminated largely by glucuronide conjugation at the 3-hydroxyl group, and the 3-methoxy group is believed to protect codeine from rapid first-pass biotransformation. Oxycodone, which also has a 3-methoxy group, has similarly good oral potency.
Many of the semisynthetic morphinan derivatives which have been prepared involve only small modifications of easily changed peripheral groups, e.g., hydromorphone, oxymorphone, oxycodone, and hydrocodone. All are narcotic analgesics like morphine and codeine, and all exhibit some measure of addiction liability.
A number of compounds possessing only a portion of the morphine ring nucleus have also been prepared. Archer, Belg. Pat. No. 611,000, discloses 2-dimethallyl-5,9-dimethyl-2'-hydroxybenzomorphan, commonly called pentazocine. Meperidine, 1-methyl-4-phenyl-4-piperidine-carboxylic acid ethyl ester, and methadone, 6-(dimethylamino)-4,4-diphenyl-3-heptanone, are wholly synthetic compounds having little structural similarity to morphine. Like morphine, these compounds have analgesic properties. Unfortunately, they also have addiction potential.
Several morphinan derivatives having various substituents on the nitrogen atom have been found to exhibit narcotic antagonist as well as narcotic analgesic activity. Such compounds are referred to as agonist-antagonists. Pachter and Matossian, U.S. Pat. No. 3,393,197, disclose N-substituted-14-hydroxydihydronormorphines, including the N-cyclobutylmethyl derivative, commonly called nalbuphine. Monkovik and Thomas, U.S. Pat. No. 3,775,414, disclose N-cyclobutylmethyl-3,14-dihydroxymorphinan, commonly called butorphanol. Bentley et al., U.S. Pat. No. 3,433,791, disclose 17-(cyclopropylmethyl)-.alpha.-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro -3-hydroxy-6-methoxy-.alpha.-methyl-6,14-ethenomorphinan-7-methanol, commonly called buprenorphine.
Still other N-substituted morphinan derivatives are pure narcotic antagonists with little or no agonist activity. Lewenstein, U.S. Pat. No. 3,254,088, discloses N-allyl-7,8-dihydro-14-hydroxynormorphinone, commonly known as naloxone. Pachter and Matossian, U.S. Pat. No. 3,332,950, disclose N-substituted-14-hydroxy-dihydronormorphinones including the N-cyclopropylmethyl analog, commonly known as naltrexone. Compounds of these two patents are narcotic antagonists.
The definition of narcotic antagonism adopted in the present invention is that of Archer and Harris, in their chapter on this topic in Progress in Drug Research, Vol. 8, 1965, pages 261 to 320, Wherein narcotic antagonists are defined as compounds which "have the remarkable property of reversing the major pharmacodynamic actions of the narcotics . . . . Strictly speaking we consider a substance to be a narcotic antagonist if it can reverse the more prominent effects of morphine such as analgesia, sedation, respiratory depression, and myosis."
The N-oxides of certain morphinan derivatives are also known in the prior art, e.g., Tiffany, U.S. Pat. No. 2,813,097, discloses 3-hydroxy-N-methylmorphinan N-oxide and its utility as an analgesic. Tiffany, U.S. Pat. No. 2,813,098, discloses 3-methoxy-N-methylmorphinan N-oxide and its utility as an antitussive. Although it is stated that these N-oxides have a higher therapeutic index than the corresponding tertiary amines, there is no suggestion that the N-oxide of 3-hydroxy-N-methyl morphinan might have improved oral bioavailability relative to the parent compound.
Bartels-Keith, U.S. Pat. No. 3,299,072, discloses thebaine derivatives of the formula ##STR1## in which R.sup.1 is C.sub.1 -C.sub.4 alkyl, R.sup.2 is C.sub.1 -C.sub.4 alkyl, hydrogen, or an acyl residue from a carboxylic acid having up to 8 carbon atoms, and R is an unsaturated alkyl group or a cycloalkyl group having up to 8 carbons. These compounds have analgesic and/or narcotic antagonist activity. The reference claims the tertiary amines, the N-oxides, and various salts of the stated formula without distinguishing the N-oxides in any way. There is no mention of route of administration.
Sawa, Maeda, and Tsuji, U.S. Pat. Nos. 3,144,459 and 3,217,006, disclose the compound of the formula ##STR2## as a synthetic intermediate to 3-methoxy-4-phenoxy N-methyl-morphinan.
N-oxide derivatives of other non-morphinan analgesics have been reported. W. Graf, Swiss Pat. No. 481,124, discloses the compound of the formula ##STR3## This compound possesses analgesic, sedative, antitussive, hypotensive, and spasmolytic properties.
K. Orzechowska, Arch. Immunol. Ther. Exp. 15(2), 290 (1967), and B. Bobranski and J. Pomorski, Arch. Immunol. Ther. Exp. 14(1), 121 (1966) report the preparation of the N-oxides of certain 1-alkyl-4-phenyl-4-acyloxy piperidine compounds. The N-oxide of 1-methyl-4-phenyl-4-propionoxypiperidine HCl exhibited analgesic activity equal to that of dolantin HCl, but of longer duration. Toxicity was also less.
The N-oxides of morphine and simple morphine derivatives such as codeine, hydromorphone (dihydromorphinone), and hydrocodone (dihydro codeinone), are well known, having been reported by, among others: M. Polonovski et al, Bull. Acad. Med. 103, 174 (1930); N. H. Chang et al, J. Org. Chem. 15, 634 (1950); B. Kelentei et al, Arzneimittel-Forsch. 7, 594 (1957); K. Takagi et al, Yakugaku Zasshi 83, 381 (1963) (Chem. Abs. 59: 9224b); L. Lafon, U.S. Pat. No. 3,131,185; M. R. Fennessy, Brit. J. Pharmacol. 34, 337 (1968); M. R. Fennessy, Eur. J. Pharmacol. 8, 261 (1969); and M. R. Fennessy, J. Pharm. Pharmacol. 21, 668 (1969). Morphine N-oxide is variously reported to be either less active or inactive as an analgesic but an effective antitussive, as well as having somewhat lower toxicity than morphine. There is no indication, however, that these N-oxides were ever administered orally, nor any suggestion that they might exhibit improved oral bioavailability.
Woods, Brit. Pat. No. 1,217,296, discloses the use of a combination of morphine N-oxide and amiphenazole as an analgesic composition. The combination is said to enhance the analgesic activity of morphine N-oxide while reducing the side effects of both compounds.
Oxidative metabolism to an N-oxide which is excreted is among the many metabolic pathways which have been identified in mammals administered various tertiary amines. J. D. Phillipson et al, Eur. J. Drug Metab. Pharmacokinetics 3, 119 (1978), report that morphine and codeine are converted in part to the corresponding N-oxides by a guinea pig liver microsomal preparation, and also that these two drugs are partially metabolized to the N-oxides when administered to rats. T. Ishida et al, Drug Metab. Dispos. 7, 162 (1979), and T. Ishida et al, J. Pharmacobio-Dyn. 5, 521 (1982), report that oxycodone N-oxide is one of a number of identifiable metabolites found in the urine of rabbits administered oxycodone subcutaneously. While other metabolites were found in both free and conjugated forms, oxycodone-N-oxide was found only in the free, unconjugated form. The analgesic activity of oxycodone is believed to be due to the unchanged drug rather than the metabolites. S. Y. Yeh et al, J. Pharm. Sci. 68, 133 (1979), also report isolating morphine N-oxide from the urine of guinea pigs administered morphine sulfate.
Certain tertiary amine N-oxides are partially metabolized by reduction to the tertiary amine upon administration to test animals. R. L. H. Heimans et al, J. Pharm. Pharmacol. 23, 831 (1971) report that morphine N-oxide is partially reduced to morphine after administration to rats. T. Chyczewski, Pol. J. Pharmacol. Pharm. 25, 373 (1973), reports that the N-oxide of 1-methyl-4-phenyl-4-piperidinol propionate is partially reduced to the tertiary amine following administration to rabbits, mice, and rats. P. Jenner et al, Xenobiotica 3 (6), 341 (1973), report that nicotine-1'-N-oxide is partially reduced to nicotine in man after oral administration, but not after intravenous administration. Oral administration of nicotine-1'-N-oxide substantially avoids the first-pass phenomenon seen with oral nicotine. The reduction to nicotine which occurs in the lower gastrointestinal tract is believed to be by GI flora.
The oral administration of many drugs will elicit a substantially lesser response as compared to an equal dose administered parenterally. This reduction in potency most commonly results from the extensive metabolism of the drug during its transit from the gastrointestinal tract to the general circulation. For example, the intestinal mucosa and the liver, through which an orally administered drug passes before it enters the systemic circulation, are very active enzymatically and can thus metabolize the drug in many ways.
When an orally administered drug is rapidly metabolized to an inactive or significantly less active form by the gastrointestinal system or liver prior to entering the general circulation, its bioavailability is low. In certain instances, this problem can be circumvented by administering the drug by another route. Examples of such alternative routes include nasal (propranolol), sublingual (nitroglycerin) and inhalation (cromolyn sodium). Drugs administered by these routes avoid hepatic and gut-wall metabolism on their way to the systemic circulation.
In some instances, the presystemic metabolism of certain orally administered drugs can be overcome by derivatization of the functional group in the molecule that is susceptible to gastrointestinal or hepatic metabolism. This modification protects the group from metabolic attack during the absorption process or first pass through the liver. However, the masking group must ultimately be removed to enable the drug to exert its maximum effect, and since the masking group is released into the body, it must be relatively non-toxic. This conversion may take place in blood or tissue. These types of masked drugs are usually referred to as prodrugs.
There are a number of examples in the literature which demonstrate the feasibility of the prodrug concept. However, it is apparent from these published studies that each drug class must be considered by itself. There is no way to accurately predict which prodrug structure will be suitable for a particular drug. A derivative which may work well for one drug may not do so for another. Differences in the absorption, metabolism, distribution, and excretion among drugs do not permit generalizations to be made about prodrug design.
Many of the above morphinans and partial morphinans are potent narcotic antagonists and/or analgesics which undergo extensive gastrointestinal and/or hepatic first-pass metabolism upon oral delivery, and thus have significantly decreased oral bioavailability. The need for strong analgesics with better oral bioavailability has long been recognized. None of the references cited, nor any known reference, suggest the novel morphinan N-oxides and partial morphinan N-oxides of the instant invention, or their desirability as prodrugs of morphinans and partial morphinans. Particularly unexpected is the fact that 3-hydroxy morphinans and partial morphinans exhibit significantly improved oral bioavailability when administered as the N-oxide derivatives.